Recent studies indicate that immune function in children with autism spectrum disorder (ASD) is profoundly altered compared to developmentally healthy controls. There is a strong interface between the immune system and the neurologic network, and successful neurodevelopment is contingent upon a successful interaction between these two systems. We have identified several aspects of immune dysfunction in patients with autism compared with typically developing controls. These include a reduced response to vaccine antigens of bacterial origin, altered cytokine levels in plasma and upon stimulation of PBMC, increased levels of leptin in patients with early onset autism, and autoantibodies to brain antigens. This wide and complex variety of immune anomalies noted in our first funding period is in keeping with the broad range of phenotypes encompassed by the autism spectrum. Thus, we will build upon our earlier findings of both serologic and cellular changes in immune function. While our studies in the previous project period were aimed at a broad analysis of immune function in patients with autism, the current proposal will address the mechanisms responsible for the numerous alterations in immune homeostasis uncovered in our earlier studies. Therefore, our primary focus will be on the mechanisms responsible for such anomalies in immune function through an in depth analysis of cellular immune function. Our overall hypothesis is that patients with autism have a fundamental defect at the cellular level that ultimately leads to abnormalities in immune function and heightened susceptibility to environmental triggers. To examine this, we propose to: (1) examine longitudinally the serologic profile of children with ASD to ascertain whether the various immune changes noted in our first studies are maintained and/or deteriorating further; (2) determine which immune cell population(s) plays a critical role in the immune dysfunction seen in patients with autism;and (3) fully characterize the autoantibody response in a subpopulation of children with ASD and some mothers of children with ASD. It must be noted that due to the highly heterogeneous nature of autism, there will potentially be immunologic differences that relate to sub-groups of patients with autism. Therefore, we will carefully define the study groups based on our current data to include children with early onset autism, children with delayed onset/regressive autism, general population controls, and children with developmental disorders without ASD. The studies will be performed on CHARGE subjects formerly analyzed by our laboratory (CHARGE-BACK study). This will allow us to extend our prior studies longitudinally to determine if the immune dysregulation, such as increased leptin levels in the early onset patients, remains over time. The following aims address both the serologic and cellular aspects of immune function in patients with autism.